학술논문
Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
Document Type
Original Paper
Author
Orliaguet, L.; Ejlalmanesh, T.; Humbert, A.; Ballaire, R.; Diedisheim, M.; Julla, J. B.; Chokr, D.; Cuenco, J.; Michieletto, J.; Charbit, J.; Lindén, D.; Boucher, J.; Potier, C.; Hamimi, A.; Lemoine, S.; Blugeon, C.; Legoix, P.; Lameiras, S.; Baudrin, L. G.; Baulande, S.; Soprani, A.; Castelli, F. A.; Fenaille, F.; Riveline, J. P.; Dalmas, E.; Rieusset, J.; Gautier, J. F.; Venteclef, N.; Alzaid, F.
Source
Nature Communications. 13(1)
Subject
Language
English
ISSN
2041-1723
Abstract
Adipose tissue macrophages (ATM) adapt to changes in their energetic microenvironment. Caloric excess, in a range from transient to diet-induced obesity, could result in the transition of ATMs from highly oxidative and protective to highly inflammatory and metabolically deleterious. Here, we demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. Transient inhibition of IRF5 activity leads to a similar respiratory phenotype as genomic deletion, and is reversible by reconstitution of IRF5 expression. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.
Interferon Regulatory Factor 5 levels have been shown to increase in adipose tissue macrophages in diet-induced obesity. Here authors show that IRF5 transcriptionally represses the Growth Hormone Inducible Transmembrane Protein gene encoding a mitochondrial protein important for oxidative respiration in macrophages, thus driving the detrimental metabolic changes observed in obesity.
Interferon Regulatory Factor 5 levels have been shown to increase in adipose tissue macrophages in diet-induced obesity. Here authors show that IRF5 transcriptionally represses the Growth Hormone Inducible Transmembrane Protein gene encoding a mitochondrial protein important for oxidative respiration in macrophages, thus driving the detrimental metabolic changes observed in obesity.